Innovative strategies are needed to improve the prognosis of patients with advanced adenocarcinomas arising in the gastrointestinal tract. We have tested several approaches to biochemically modulate fluorouracil (FUra), and are studying the interaction of other agents with FUra in vitro to define optimal sequences for potential clinical use. The identification of new agents such as the camptothecin analogs that display potent in vitro and in vivo activity against GI adenocarcinomas is of paramount importance. Studies designed to elucidate the optimal schedule of administration and mechanism of action of such agents are vital to facilitate their rational clinical use. We implement Phase I clinical trials that incorporate clinical pharmacokinetic, biochemical and/or molecular endpoints. New analytic assay methods are developed to measure the pharmacokinetics and intracellular pharmacodynamics of the anticancer agents. Colorectal cancer cells appear to have an extraordinary capacity to recover from the metabolic and/or genotoxic stress imposed during a transient cytotoxic insult. The refractory nature of human colorectal cancer may be attributed to differences in the cellular response to genotoxic stress such as DNA synthetic inhibition and/or DNA damage, and an impaired ability to undergo programmed cell death. These molecular phenotypes result from mutations in several key genes including p53, ras, and genes coding for proteins involved in DNA mismatch repair. Our ultimate goal is to develop new agents and drug combinations for patients with GI adenocarcinomas and to develop strategies to selectively target cancer cells with genomic instability and/or impaired programmed cell death pathways.